Biomedical subjects
Publications and source records attributed to H Takashima.
Introduction of acyclic chain for synthesis of acyclonucleoside derivatives was achieved in a simple and convenient way. Silylated pyrimidine or purine bases were treated with 1,3-dioxolane, trimethyl chlorosilane and metal iodide, such as KI and NaI, all together at room temperature. By this method, 2-thiopyrimidine derivatives were also obtained in good yield, using 2 molecular equivalents of 1,3-dioxolane.
To elucidate the clinical characteristics of pulmonary edema in unstable angina, 120 patients with unstable angina who admitted to the hospital within 6 hours after the onset of chest pain were studied. The criteria for the diagnosis of pulmonary edema included interstitial pulmonary edema and diffuse alveolar edema. Pulmonary edema was present in 24 patients. In these patients, the duration of chest pain was relatively longer, and the incidences of diabetes mellitus, emergency coronary revascularization and multiple-vessel coronary artery disease were higher than in those without pulmonary edema. In addition, in-hospital mortality rate in patients with pulmonary edema was higher than in those without it (21 vs 1%, p < 0.001), which is probably due to a large area of myocardial ischemia. For these patients, therefore, early diagnosis and appropriate therapy to save viable segments of the myocardium are mandatory.
We made three different lines of hepatitis B virus (HBV) transgenic mice which express different amounts of hepatitis B e antigen (HBeAg) and/or hepatitis B core antigen (HBcAg) to analyse the cellular mechanisms of HBcAg specific T-cell tolerance. BS10 (official designation, 1.2HB-BS10) transgenic mice, which contain the whole HBV genome, express relatively high amounts of HBeAg in the serum and HBcAg in the liver. SPC mice, which contain hepatitis B virus core and precore gene, express small amounts of HBeAg in the serum but not HBcAg in the liver. SC33 mice, which contain only hepatitis B core gene, do not express HBeAg in the serum but express HBcAg in the liver. BS10 mice showed a very low anti-HBc antibody response after primary and secondary immunizations with recombinant HBcAg compared to transgenic host C57BL/6 (B6) mice. SPC mice showed an almost equal level of anti-HBc antibody response compared to B6 mice. SC33 mice contained anti-HBc antibody even before immunization and showed high titres of anti-HBc antibody response after immunization with HBcAg. Analysis of cellular site(s) of low responsiveness of BS10 mice revealed that proliferating and helper T cells are specifically tolerant to HBcAg. B cells and antigen-presenting cells in BS10 mice were not defective. SC33, SPC and BS10 mice differ a little in their developmental expression of HBc/HBeAg. Our results suggest critical roles of the nature (circulating versus non-circulating) as well as the time of expression of self-antigens in T-cell tolerance.
The correlation between patient visits and meteorological parameters were analyzed regarding asthmatic children who visited the outpatient emergency clinics at Teikyo University Hospital in Tokyo and Ogaki Municipal Hospital in Gifu, during the two years of 1986 and 1987. The yearly climatological changes are quite similar in both areas. Moreover, variations in the number of patient visits were also remarkably similar in both areas. High temperatures and high vapor pressure significantly correlated with increased numbers of visits in both areas. High humidity and high barometric pressure had some correlation with increased numbers of visits in both areas. As for wind direction, northerly synoptic winds had a significant correlation with increased numbers of visits in Tokyo, while contrarily, southerly winds produced the same effect in Ogaki. Precipitation and cloud density showed no correlation with the number of patient visits in either area.
In the search for 1-[(2-hydroxyethoxy)-methyl]-6-(phenylthio)thymine (HEPT) derivatives, we have found several 5-ethyl-6-(phenylthio)uracil analogues to be highly potent and selective inhibitors of human immunodeficiency virus (HIV) type 1. 1-Benzyloxymethyl-5-ethyl-6-phenylthiouracil, the most potent congener of the series, inhibits HIV-1 replication in a variety of cell systems, including peripheral blood lymphocytes, at a concentration of 1.5-7.0 nM, which is lower by a factor of 10(3) than the 50% antivirally effective concentration of the parent compound HEPT. The 5-ethyl-6-(phenylthio)uracil analogues, like HEPT itself, do not inhibit HIV-2 replication but do inhibit replication of 3'-azido-3'-deoxythymidine-resistant mutants of HIV-1. 1-Benzyloxy-methyl-5-ethyl-6-phenylthiouracil and its congeners are targeted at the HIV-1 reverse transcriptase (RT). They do not inhibit HIV-2 RT. They do not need to be metabolized to exert their inhibitory effect on HIV-1 RT. Yet this inhibitory effect is competitive with the natural substrate dTTP. The HEPT derivatives represent a group of RT inhibitors with a unique mode of interaction with HIV-1 RT.
Neurotoxic peptides from venoms of scorpions and honey bees exhibit a consensus pattern in the two disulfide bridgings related to the sequence portions Cys-X-Cys and Cys-X-X-X-Cys. A revised three-dimensional structure of charybdotoxin, as determined by two-dimensional nmr spectroscopy, confirms that the consensus cystine dislocation generates in all these toxins a common structural element, i.e., the cystine-stabilized alpha-helical (CSH) motif, which may be correlated with their common ion channel blocking activity.
In animal models, grafts derived from several different tissues, principally fetal substantia nigra and adrenal medulla from young adults, have been found to be effective in alleviating some of the manifestations of lesions of the substantia nigra. It has been suggested that these grafts function by diffusely secreting dopamine, by exerting trophic effects on the host brain, or by producing a new innervation of the host corpus striatum. Evidence for each of these modes of action is briefly reviewed. Several brain tissue transplantation techniques have been described. Each of these techniques has significant limitations in animal models. The significance of these limitations for human application is described, and possibilities for improving the efficacy of brain tissue transplantation in animal models and for human application are discussed.
Fourteen patients with HTLV-1-associated myelopathy were treated with high-dose intravenous gammaglobulin (IVGG). Ten received 10 g/day of IVGG and 4 received 400 mg/kg of body-weight/day of IVGG for 5 consecutive days. Improvement of spastic paraparesis was observed in 10 within 7 days of the commencement of IVGG. The therapeutic effects were sustained for more than 3 weeks in some patients. There were no side effects. Analysis of factors of relevance to the clinical improvement with IVGG showed that the beneficial response was preferentially found in patients having a high CSF titre of anti-HTLV-I antibodies, a high CSF IgG level and a marked brain MRI abnormality.
The relation of mixed venous oxygen saturation and the cardiac index to tissue oxygenation and prognosis was investigated in 119 patients with acute myocardial infarction. There was a positive correlation between mixed venous oxygen saturation and the cardiac index in 97 survivors and 22 nonsurvivors, but a significantly lower mixed venous oxygen saturation level at the same level of cardiac index was observed in nonsurvivors compared with survivors. Results of multivariate analysis with mixed venous oxygen saturation and the cardiac index indicated that only mixed venous oxygen saturation was significantly related to survival and to hyperlactacidemia. Oxygen delivery to tissues declined significantly in nonsurvivors because of a lower cardiac index and a lower hemoglobin concentration in these patients than in survivors. However, at the same level of oxygen delivery to tissues, nonsurvivors had a significantly higher rate of oxygen consumption leading to a correspondingly greater decrease in mixed venous oxygen saturation, suggesting that a greater increase in oxygen demand was also observed in nonsurvivors than in survivors. Thus mixed venous oxygen saturation after acute myocardial infarction is a better predictor of hyperlactacidemia and survival than the cardiac index, and this may be associated with an increased oxygen demand and an impaired oxygen transport system in seriously ill patients.
A series of novel acyclouridine derivatives substituted at both the C-5 and C-6 positions were synthesized for the purpose of improving the activity of a recently reported HIV-1-specific lead, 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT). Preparation of C-6 substituted derivatives was carried out based on the following three methods: (1) LDA (lithium diisopropylamide) lithiation of a thymine derivative (4) and subsequent reaction with electrophiles, (2) an addition-elimination reaction of HEPT or its 6-(phenylsulfinyl) derivative (10), or (3) palladium-catalyzed cross-coupling between a 6-iodo derivative (16) and terminal alkynes. Following the methods, 21 C-6 substituted analogues were synthesized. Among these, 6-(cyclohexylthio) (8), 6-phenoxy (13), and 6-benzyl (27) derivatives showed anti-HIV-1 (HTLV-IIIB) activity with EC50 values of 8.2, 85, and 23 microM, respectively. Preparation of C-5 substituted derivatives was based on either LTMP (lithium 2,2,6,6-tetramethylpiperidide) lithiation of 6-(phenylthio)uracil derivative 37 or the above mentioned palladium-catalyzed cross-coupling of a 5-iodo-6-(phenylthio)uracil derivative (38). Following these methods, 11 C-5 substituted analogues were synthesized. Some 5-substituted derivatives (5-I, 44; 5-CH = CPh2, 49; 5-CH = CHPh (Z), 54; and 5-CH = CH2, 55) were more active than HEPT, but their selectivity indices (SI = CC50/EC50) were lower than that of HEPT. Compound 8 was also evaluated against another HIV-1 strain (HTLV-IIIRF) and HIV-2 strains (LAV-2ROD and LAV-2EHO). Only HTLV-IIIRF was as sensitive as HTLV-IIIB.
Several analogues of a new lead for anti-HIV-1 agents, 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT), in which the C-2, N-3, or C-4 position was modified were synthesized. These involve 2-thiothymine (11), 2-thiouracil (12), 4-thiothymine (17), 4-thiouracil (18), 5-methylcytosine (27), and cytosine (28) derivatives. Preparation of N-3-substituted derivatives (29 and 30) of HEPT was also carried out. Among these analogues, compound 11 exhibited excellent activity against HIV-1 HTLV-IIIB strain with an EC50 value of 0.98 microM, which is 7-fold more potent than that of HEPT. Removal of the 5-methyl group in compound 11 results in total loss of activity. Other compounds did not show any anti-HIV-1 activity. The 4-thio derivatives 17 and 18 were found to be rather cytotoxic. When compound 11 was evaluated for its inhibitory effects on another HIV-1 strain, HTLV-IIIRE, and two HIV-2 strains, LAV-2ROD and LAV-2EHO, it proved equally inhibitory to HTLV-IIIRF, whereas both HIV-2 strains were insensitive to the compound.
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The existence of mixed haplotype A beta dA alpha b and mixed isotype A beta dE alpha d molecules was demonstrated in A beta d gene introduced C57BL/6 (B6) transgenic and in A beta dE alpha d double gene introduced B6 transgenic mice, respectively. Using alloreactive and antigen reactive T-cell clones, these mixed class II molecules were shown to function as mixed lymphocyte culture reaction (MLR) stimulating determinants and restriction elements for antigen recognition by T cells. The amounts of expression of these mixed class II molecules were sufficient for the stimulation of alloreactive T cells in primary MLR culture. (BALB/c x B6)F1 (CBF1) mice were shown not to express functional mixed haplotype and mixed isotype class II molecules using alloreactive and antigen reactive T-cell clones. Interestingly, however, CBF1 mice did not respond to such mixed haplotype and mixed isotype class II molecules. These results show that CBF1 mice do not respond to undetectably-expressed class II molecule and suggest that they are tolerant to undetectable self class II molecules. The possible interpretations for this are discussed.
Conformational analysis of neocarzinostatin, an antibiotic protein with antitumor activity, in its holo-state in solution was carried out by NMR-spectroscopy. The results showed a beta-barrel structure for the carrier protein, in which the chromophore is tightly enwrapped and thus shielded from exposure to the solvent. The three-dimensional structure of this complex led to the proposal of a possible mechanism for the exposure or release of the active principle due to subtle environmental changes, e.g., in pH.
OBJECTIVE: To evaluate the clinical characteristics of increased extravascular lung water (EVLW) in patients with low pulmonary artery occlusion pressure (PAOP) in the early phase of acute myocardial infarction. DESIGN: Consecutive sample for descriptions of the clinical features of medical disorders. SETTING: A general medicine group practice in a university hospital. PATIENTS: Sixteen patients with low PAOP (less than 18 mm Hg) on the initial measurement obtained within 12 hr of chest pain onset. MEASUREMENTS AND MAIN RESULTS: EVLW was measured by the thermal indocyanine green dye double-indicator dilution method. QRS score was obtained on hospital day 7 from the Selvester's QRS Scoring System. Eleven (69%) patients had increased EVLW greater than 7 mL/kg despite low PAOP. EVLW had no significant correlation with PAOP and the difference between plasma colloid osmotic pressure and PAOP, but did have a significant correlation with pulmonary vascular resistance index (r2 = .31, p less than .05), and QRS score (r2 = .45, p less than .005). CONCLUSIONS: Larger infarcts led to increased EVLW even with low PAOP, and the accumulation of increased EVLW around the small arterioles might have led to increased pulmonary vascular resistance.
Two patients with "pure akinesia" who showed the characteristic changes of progressive supranuclear palsy (PSP) at necropsy are described. They had akinesia but no rigidity or tremor, and ophthalmoplegia was not observed during the course of illness. The symptoms of "pure akinesia" was not improved by levodopa therapy but was considerably improved by L-threo-3,4-dihydroxy-phenylserine. At necropsy, pathological findings were not different from those reported for PSP. It is suggested that "pure akinesia" is an atypical manifestation of PSP, and that norepinephrinergic neurons may be involved in some types of PSP.
To evaluate the difference in the frequency of complication of mitral valve prolapse (MVP) according to sex in subjects aged 60 years and older, 543 patients (218 men and 325 women) who were diagnosed as having MVP by echocardiography at the Lahey Clinic Medical Center were studied. Three hundred and fourty eight patients had no complication of MVP (male vs female = 129:219). Infective endocarditis occurred in 20 patients (male vs female = 13:7). Rupture of chordae tendineae occurred spontaneously in 29 patients (male vs female = 20:9) and were associated with infective endocarditis in 8 other patients (male vs female = 6:2). Eighteen patients required mitral valve surgery for severe mitral regurgitation. The frequencies of these complications were higher in males than those in females. Cerebral ischemic events were encountered in 54 patients. There was no significant difference in the frequency between male and female. In conclusion, MVP in elderly men might be at for cardiac complication.
We demonstrated the existence of mixed isotype A beta E alpha class II molecules in Ed alpha gene-introduced C57BL/6 (B6Ed alpha) transgenic mice. Immunoprecipitation and two dimensional (NEPHGE/SDS-PAGE) gel electrophoresis analysis of labeled B6Ed alpha spleen cell lysates using monoclonal anti-Ab beta antibody showed Ed alpha spots in addition to Ab beta and Ab alpha spots. We obtained alloreactive T cell clones from B6 anti-B6Ed alpha long-term cultures that recognized the Ab beta Ed alpha molecule. We also obtained antigen reactive T cell clones that recognized antigen in the context of Ad beta Ed alpha mixed isotype class II molecules. The importance of the mixed isotype class II molecules in relation to the expansion of the T cell specificity repertoire as well as autoimmune induction is discussed.